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TitleStructural basis for the subtype-selective activation of K3.1 channels.
Journal, issue, pagesStructure, Year 2026
Publish dateMay 14, 2026
AuthorsAlena Ramanishka / Joshua A Nasburg / Yang Xu / Xinyi Ma / Reza Mehvar / Meng Cui / Young-Woo Nam / Heike Wulff / Miao Zhang /
PubMed AbstractThe intermediate-conductance (K3.1) and the small-conductance (K2.2) Ca-activated K channels share a Ca-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K3.1 ...The intermediate-conductance (K3.1) and the small-conductance (K2.2) Ca-activated K channels share a Ca-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K3.1 and K2.2 in complex with two benzothiazole-type activators. While SKA-31 is only moderately selective (∼7.3-fold), its derivative SKA-111 exhibits ∼70-fold selectivity for K3.1 over K2.2. SKA-31 and SKA-111 both bind in a pocket at the interface between the SA helix and calmodulin where they allosterically modulate the inner gate of the two channels. SKA-31 binds with comparable energies in the two channels, consistent with its moderate selectivity for K3.1 over K2.2. In the K3.1 structure, the calmodulin helix IV is positioned outward, forming a pocket that more readily accommodates the bulkier SKA-111 that sits deeper inside calmodulin's N-lobe in K3.1 than in K2.2. The resulting higher binding energy explains the improved selectivity of SKA-111 for K3.1 compared to the less selective SKA-31.
External linksStructure / PubMed:42140186
MethodsEM (single particle)
Resolution2.77 - 3.67 Å
Structure data

74531

9zpo

EMDB-74531, PDB-9zpo:
Cryo-EM structure of KCa3.1_I/calmodulin channel in complex with SKA31.
Method: EM (single particle) / Resolution: 3.67 Å

74533

9zpt

EMDB-74533, PDB-9zpt:
Cryo-EM structure of KCa3.1_II/calmodulin channel in complex with SKA31.
Method: EM (single particle) / Resolution: 3.39 Å

74625

9zrk

EMDB-74625, PDB-9zrk:
Cryo-EM structure of KCa3.1_I/calmodulin channel in complex with SKA111.
Method: EM (single particle) / Resolution: 2.99 Å

74626

9zrl

EMDB-74626, PDB-9zrl:
Cryo-EM structure of KCa3.1_II/calmodulin channel in complex with SKA111.
Method: EM (single particle) / Resolution: 3.38 Å

74627

9zrq

EMDB-74627, PDB-9zrq:
Cryo-EM structure of KCa2.2/calmodulin channel in complex with SKA31.
Method: EM (single particle) / Resolution: 2.77 Å

74628

9zrr

EMDB-74628, PDB-9zrr:
Cryo-EM structure of KCa2.2/calmodulin channel in complex with SKA111.
Method: EM (single particle) / Resolution: 3.31 Å

Chemicals

PDB-1c3q:
CRYSTAL STRUCTURE OF NATIVE THIAZOLE KINASE IN THE MONOCLINIC FORM

ChemComp-CA:
Unknown entry

ChemComp-K:
Unknown entry

PDB-1c3u:
T. MARITIMA ADENYLOSUCCINATE LYASE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Intermediate conductance calcium-activated potassium channel / Ion channel / Calmodulin binding protein / TRANSPORT PROTEIN

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